Genetic factors do not fully account for the relatively high heritability of neurodevelopmental conditions, suggesting that non-genetic heritable factors contribute to their etiology. To evaluate the potential contribution of aberrant thyroid hormone status to the epigenetic inheritance of neurological phenotypes, we examined genetically normal F2 generation descendants of mice that were developmentally overexposed to thyroid hormone due to a Dio3 mutation. Hypothalamic gene expression profiling in postnatal day 15 F2 descendants on the paternal lineage of ancestral male and female T3-overexposed mice revealed, respectively, 1089 and 1549 differentially expressed genes. A large number of them, 675 genes, were common to both sets, suggesting comparable epigenetic effects of thyroid hormone on both the male and female ancestral germ lines. Oligodendrocyte- and neuron-specific genes were strongly overrepresented among genes showing, respectively, increased and decreased expression. Altered gene expression extended to other brain regions and was associated in adulthood with decreased anxiety-like behavior, increased marble burying and reduced physical activity. The sperm of T3-overexposed male ancestors revealed significant hypomethylation of CpG islands associated with the promoters of genes involved in the early development of the central nervous system. Some of them were candidates for neurodevelopmental disorders in humans including Nrg3, Nrxn1, Gabrb3, Gabra5, Apba2, Grik3, Reln, Nsd1, Pcdh8, En1, and Elavl2. Thus, developmental levels of thyroid hormone influence the epigenetic information of the germ line, disproportionately affecting genes with critical roles in early brain development, and leading in future generations to disease-relevant alterations in postnatal brain gene expression and adult behavior.
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We are grateful to Joseph Nadeau for his critical review of the manuscript and to Amanda Drake for technical advice. This study was supported by grants MH096050 and DK095908 from the National Institute of Mental Health and National Institute of Diabetes, Digestive and Kidney Diseases, respectively. This work used the Confocal Microscopy Core, the Histopathology Core, the Physiology Core and the Molecular Phenotyping Core at Maine Medical Center Research Institute, that are supported by grants P30GM106391, P30GM103392, P20GM121301, and U54GM115516 from the National Institute of General Medical Sciences.
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The authors declare that they have no conflict of interest.
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Martinez, M.E., Duarte, C.W., Stohn, J.P. et al. Thyroid hormone influences brain gene expression programs and behaviors in later generations by altering germ line epigenetic information. Mol Psychiatry 25, 939–950 (2020). https://doi.org/10.1038/s41380-018-0281-4
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